Hormonal peptides are an important class of secreted signaling molecules. Endogenous peptides are most notable for their functions in innate defense as antimicrobial peptides (Cederlund et al., 2011), in immune regulation as chemokines (Bonecchi et al., 2009) and in modulation of behavior as neuropeptides (van den Pol, 2012). Deficiencies in hormonal peptides are the cause of several human diseases, the most prominent being the loss of INSULIN or INSULIN resistance in diabetes mellitus. Deficiency in the neuropeptide HYPOCRETIN causes narcolepsy (Nishino et al., 2000; Peyron et al., 2000) while anomalies in the regulation of the appetite and satiety hormones LEPTIN (Montague et al., 1997) and GHRELIN are the underlying causes for congenital obesity and hyperphagia in Prader-Willi syndrome (Cummings et al., 2002).
The discovery of new peptide-encoding genes is challenging, since their open reading frames (ORFs) are small and often overlooked by size-biased ORF prediction algorithms. This limitation has lead to their under-prediction or classification as non-coding transcripts (Frith et al., 2006). Equally challenging is the matching of these hormones to their cognate cell surface receptors. The vast majority of small signaling peptides are known to bind and signal through G-coupled protein receptors (GPCRs), the largest family of cell surface receptors (Rasmussen et al., 2007). GPCRs can be broadly classified into two categories based on the source of their ligands (Vassilatis et al., 2003). Chemosensory-GPCRs sense environmental cues such as odorants, tastants and pheromones, while endo-GPCRs transduce signals originating from endogenous compounds such as peptide hormones, amines, nucleosides or lipids. Recent studies estimate the number of endo-GPCRs in the human genome to be close to 370 (Vassilatis et al., 2003). Approximately 140 of these (40%) have no known ligands and are therefore orphaned GPCR receptors. As such, the discovery and pairing of novel endogenous hormones to their cognate receptors remains a considerable endeavour.
Whereas many peptide hormones have been characterized and shown to play key roles in adult physiology, an involvement for these tiny signaling molecules during early development has not been established. During embryogenesis, six key signaling pathways namely WNT, BMP/NODAL, FGF/IGF, NOTCH, HEDGEHOG and HIPPO are crucial for embryonic patterning. In particular IGF/FGF and NODAL are essential for maintaining pluripotency in human embryonic stem cells (hESCs) (Dalton, 2013). Aside from INSULIN/IGF, FGF and TGFβ/ACTIVIN/NODAL, no other soluble factors have been isolated from feeder or hESC-conditioned media and proven to be necessary for hESC culture (Hughes et al., 2011).
To our knowledge, no hormonal peptide has ever been implicated in maintaining the self-renewal capacity of hESCs or their ability to differentiate into any of the three embryonic germ layers.